Effectiveness of Lymphoscintigraphic Sentinel Node Detection for Cervical Staging of Patients With Squamous Cell Carcinoma of the Head and Neck

J Oral Maxillofac Surg 63:1091-1095, 2005

Effectiveness of Lymphoscintigraphic Sentinel Node Detection for Cervical Staging of Patients With Squamous Cell Carcinoma of the Head and Neck Pierre Payoux, MD,* Celine Dekeister, MD,† Raphaël Lopez, MD,‡ Frédéric Lauwers, MD,§ Jean Paul Esquerré, MD, PhD,储 and Jean Roch Paoli, MD¶ Purpose: To evaluate the feasibility and staging ability of the sentinel node (SN) technique for patients

with squamous cell carcinoma of the oral cavity or oropharynx and clinically negative necks. This prospective study compares the histopathologic status of the SN with that of the remaining neck dissection tissues. Patients and Methods: Thirty previously untreated patients with T1 to T4 squamous cell carcinoma of the oral cavity or oropharynx and clinically negative necks (N0) were included in the study. Injection of 99m Tic-radiolabeled sulfur colloid around the primary tumor and lymphoscintigraphy were performed the day before surgery. Intraoperatively, the SN(s) was localized with a gamma probe and removed during neck dissection. The tumor was resected at the same time. Results: For 1 patient, lymphoscintigraphy revealed no SN. SN were identified in 29 patients/37 necks. In 29 necks, there were no positive SN. In 5 patients, the SN was the only histopathologically positive node. In 1 patient, SN and other nodes in the remaining neck tissue were positive. There was 1 false negative case; the first case of the study, indicating the need for a learning curve for the technique. Conclusion: This prospective study shows that the SN is useful for the staging of N0 necks. The SN technique has the potential to decrease the need for neck dissections, which are usually performed in clinically negative necks, thus reducing both associated morbidity for patients and cost. © 2005 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 63:1091-1095, 2005 Because cancers of the aerodigestive mucosa are highly lymphophilic, the tumor and lymph nodes *Clinical assistant, Department of Nuclear Medicine, Purpan Hospital, Toulouse, France. †Resident, Department of Oral and Maxillofacial Surgery, Purpan Hospital, Toulouse, France. ‡Resident, Department of Oral and Maxillofacial Surgery, Purpan Hospital, Toulouse, France. §Resident, Laboratory of Computer Assisted Surgery, CRAO, Toulouse, France. 储Clinical professor, Department of Nuclear Medicine, Purpan Hospital, Toulouse, France. ¶Clinical professor, Department of Oral and Maxillofacial Surgery, Purpan Hospital, Toulouse, France. Address correspondence and reprint requests to Dr Paoli: Purpan University Hospital, TSA 40031, 31059 Toulouse Cedex 9, France; e-mail: [email protected] © 2005 American Association of Oral and Maxillofacial Surgeons

0278-2391/05/6308-0006$30.00/0 doi:10.1016/j.joms.2005.04.026

must be managed even if there are no visible or palpable metastases. In such a situation (patients staged TXN0M0), the risk of occult lymph nodes ranges from 10% to 30% or more according to the authors and depending on the site of the tumor and certain histologic parameters.1 Many teams consider that such a risk justifies selective neck dissection. Even limited, this neck dissection investigation may potentially cause sequelae. If metastases are discovered, neck dissection can be completed as necessary and appropriate external radiotherapy can be proposed. The presence of cervical metastases remains the principal prognostic factor of these cancers, so awareness of lymph node status is important for optimal management of the disease. To minimize the sequelae of neck dissections, of which at least 70% are carried out on necks that are in fact negative, detection methods more sensitive than clinical examination or imaging techniques are required. At the present time, as such methods do not exist, the sentinel node (SN) technique proposes excision restricted to the

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first draining lymph nodes. The rationale behind this technique is based on the postulate that invasion spreads sequentially and firstly involves the first drainage node. This technique is routinely used for management of malignant cutaneous melanoma and has been validated. It is being studied for the management of squamous cell carcinomas of the upper aerodigestive tract. Here we present the results of this technique in 30 patients operated for squamous cell carcinoma of the head and neck.

Patients and Methods PATIENTS

From October 2002 to January 2004, sentinel lymph node detection was carried out in 30 patients with squamous cell carcinoma of the oral cavity and oropharynx. Gender ratio was 3 men/1 woman, age 58 ⫾ 10 years. All patients were previously untreated and had N0 necks as assessed by palpation and iodine injected computed tomography scan. All patients underwent clinical examination under general anesthesia for assessment of clinical stage. Medical files were discussed before lymphoscintigraphy in multidisciplinary working sessions which decided the surgical procedure. Tumor resection and cervical neck dissection was carried out for levels I, II, III, and IV, bilaterally when the tumor was near the midline. All tumors were classified N0 according to International Union Against Cancer (UICC) criteria and were staged as follows: 3 T1, 17 T2, 2 T3, and 5 T4. Sites are shown in Table 1. Tumors classified as T4 were not extended lesions but mainly included jawbone or gum lesions that had early invaded bone. In all cases, biopsy confirmed squamous cell carcinomas: 22 cases were well differentiated, 6 were moderately differentiated, and 1 was undifferentiated. METHODS

Patients underwent lymphoscintigraphy approximately 18 hours before surgery. After local anesthesia Table 1. TUMOR SITES IN 30 PATIENTS WITH SQUAMOUS CELL CARCINOMA OF THE ORAL CAVITY AND OROPHARYNX

Tongue Floor of mouth Floor ⫹ tongue Trigone Internal cheek Palate Gingival

8 10 4 1 1 2 4

Payoux et al. Sentinel Node in Squamous Cell Carcinoma. J Oral Maxillofac Surg 2005.

FIGURE 1. Lymphoscintigram acquired in the left anterior oblique (A), right anterior oblique (B), and posterior projection (C) of a patient with a left tongue carcinoma. Arrows point to left cervical sentinels nodes. Notice the importance of the triple projections to locate nodes. Payoux et al. Sentinel Node in Squamous Cell Carcinoma. J Oral Maxillofac Surg 2005.

with 10% lidocaine spray, 50 or 75 MBq 99mTc-radiolabeled sulfur colloid (Nanocis; Cis bio International, Saclay, France), particle size 100 nm, suspended in 0.2 mL saline was administered by 3 or 4 peritumoral submucosal injections (1 syringe for each injection), depending on the size and accessibility of the primary tumor. The injections were carried out by the nuclear physician in the Department of Nuclear Medicine. The syringes used had permanently secured needles to prevent inadvertent spillage of colloid into the mouth. Immediately following injection, the patients were asked to use a mouthwash to prevent the tracer remaining in the pharynx or esophagus. A few minutes (1 to 4) after the injections, dynamic lymphoscintigraphy images were obtained (30 ⫻ 60 seconds, 128 ⫻ 128 matrix, low-energy high-resolution collimator) with an IRIX triple-detector camera (Philips, The Netherlands). The patient lay supine and the 3 detectors were placed in a posterior and left and right oblique positions. Following the dynamic scan, we obtained 3 simultaneous early static images after 10 minutes using the posterior and the left and right anterior heads of the camera (Fig 1). Further static images were obtained 2 to 3 hours later. SNs were defined as nodes clearly localized in different basins, visible within 15 minutes of dynamic lymphoscintigraphy or in early static imaging. The locations of radioactive lymph nodes were localized on the patients’ skin using a 57Co solid source pen

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which could be seen on the 3 heads of the camera’s persistence display. This position was then marked on the skin using indelible ink. The position of the SN was confirmed with a hand-held gamma probe (Europrobe, Cis bio International, Schering). Thirty patients were operated under general anesthesia for a total of 37 neck dissections, taking into account midline lesions. The tumor was resected first when this could be performed by a natural approach to avoid the risk of error related to residual radioactivity at the injection site. Neck dissection was then performed by the usual technique, removing levels I, II, and III. The SN was precisely located during this procedure but was removed on the operating table at the end of the dissection process. The SN or nodes were examined, as was the rest of the sample, by frozen section. If this was positive, levels IV and V were also removed. During the procedure, a dosimeter was carried by the surgeon. The final histologic examination was carried out according to the following protocol: Each SN identified intraoperatively was systematically examined by frozen section and then secondarily on paraffin sections after fixing in 10% formalin. Gross examination revealed the number, location, and size of the SN or nodes. Each lymph node was examined intraoperatively (immediate examination) on 3 serial frozen sections. When the SN was large, it was first cut in half (or more) and each half was examined by frozen section. The sample was then thawed and fixed in 10% formalin for 12 hours before it was embedded in paraffin for control. Each SN was examined on 2 serial paraffin sections after staining with hemalum-eosin. Immunohistochemical study was not performed. The other lymph nodes in the same sample were examined in the same way. The final report indicated the number of nodes examined, their location, size, presence or absence of metastases, and extra-capsular spread.

Results The results thus concern 30 patients and 37 necks. In 1 case of gingival cancer, scintigraphy did not reveal a lymph node. All lymph nodes were detected in early dynamic images, and later images yielded no further information. Initial scintigraphy revealed 1 lymph node in 19 necks, 2 lymph nodes in 8 necks, and 3 lymph nodes in 10, a mean of 1.8 lymph nodes per neck. The number of lymph nodes detected did not depend on the site or the size of the tumor. Of the 64 SNs revealed by preoperative scintigraphy, 63 were identified and excised during the surgical procedure. The radiation dose recorded by the dosimeter was always less than 2 ␮Sv. The mean number of

nodes examined in the operative specimens was 21 (range, 12 to 40). The results of the final histologic investigations were as follows: In 29 necks, both SN and neck dissection were negative. Seven patients had metastases (25% of patients, 20% of necks studied). Among these, for 5 patients only the SN was positive (2 positive SNs for 1 of these 5 patients), and the rest of the neck was negative. This represents 6 metastatic nodes for 106 nodes examined. One patient had 1 positive SN and 2 lymph node metastases on neck dissection. Lastly, 1 patient had 1 negative SN, while the rest of the neck dissection presented 3 metastases. Overall, this method enabled us to stage 6 of 7 positive patients (86%). It was noteworthy that the false negative was the first case in the series. Of the positive lymph nodes, 3 contained a micrometastasis (less than 2 mm in diameter). The others had larger metastases, but without extra-capsular spread.

Discussion Squamous cell cancers are highly lymphophilic and extension to the lymph nodes is a major prognostic factor. Most teams consider that selective neck dissection is required in patients in whom classic investigations (magnetic resonance imaging, computed tomography scan, and clinical examination) do not show lymph node involvement. Even if this type of investigation is restricted, it can lead to a number of sequelae. Also, it modifies the drainage system which is in fact finally an effective system of protection in this type of tumor. The classic risk of 30% occult metastases in N0 patients is probably higher. Recent anatomopathologic studies using immunohistochemical and molecular analysis methods have shown that neck dissections classified pN0 with conventional methods had in fact much more frequent early involvement.2 These findings explain the need for better knowledge and more effective means of detection to avoid a surgical procedure that is often useless and sometimes leads to undesirable sequelae,3 profoundly modifying the lymphatic system. In such a context, the SN technique can improve the management of these patients. This technique seems to be more and more frequently used for the management of squamous cell cancers of the upper aerodigestive tract.4 The studies published to date are encouraging and support the pursuit of this research. Some studies have been carried out using patent blue dye injection, but this method does not seem to be easy to use. Several teams combine both techniques.5 We did not use patent blue dye in our study. This use of blue dye technique requires a large cutaneous incision that is

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in opposition to the idea of minimally invasive surgery supported by radiolocalization. Technical questions arise, however, regarding the choice of colloid, the dose to be used, and the injection technique. We chose high molecular weight particles to obtain prolonged accumulation in the first echelon draining lymph nodes. The SN rapidly became visible. Late images did not reveal a new underlying hot spot, thus confirming the rapid, prolonged accumulation of the colloid up to the time of the procedure. The teams who have carried out such research emphasize a learning curve, as the unsatisfactory results (SN⫺ND⫹) were often recorded among the first cases.4,6 This occurred in our series, as the only false negative recorded was our first case. Once this detection method has been mastered, a process that involves the whole team, from the pharmacist to the surgeon and including the specialist in nuclear medicine, it seems to give particularly promising results. It enabled us to locate 6 involved lymph nodes among the 106 examined in 5 patients. This result shows the potential of this method. Sensitivity in our series was only 86%, but in a small number of positive cases. In some series, it is more than 90%. The published results of the First International Conference on SN Biopsy in Mucosal Head and Neck Cancer in June 2001,4 summarizing the work of 22 centers (comparison between SN status and neck dissection) showed the following results for the 316 N0 necks included. Three hundred one SN were identified (95%). Seventy-six of these (25%) were positive, with a sensitivity of SN detection of 90%. The need for a learning curve was also shown, as sensitivity ranged from 57% for centers that had less than 10 cases to 94% for the most experienced teams. Since then, a

certain number of publications have confirmed the interest of this technique. The principal results are shown in Table 2, and detailed analysis shows they corroborate those of the Congress (the first International Conference on SN Biopsy in Mucosal Head and Neck Cancer, Glasgow, June 2001). Once the technique has been mastered, it enables correct staging in over 90% of cases. These results could perhaps be even further improved by pursuing histologic examination of the SN with immunohistochemical and biomolecular analysis techniques.2 According to recent works, the type of metastasis must also be taken into account. In his studies, Stoeckli et al7 differentiates positivity according to the diameter of the metastases using Hermanek’s criteria.8 This certainly has implications for treatment and prognosis that should be addressed in future studies. For the time being, search for the SN has not affected our treatment protocol since we carried out the usual neck dissection, which was completed if a positive node was found on frozen section. Among the occult metastases that were detected in this way, we found a non-negligible proportion of micrometastases. We believe that this should restrict the fine-needle aspiration biopsies proposed by some authors in association with SN detection.9,10 Lastly, this technique is potentially cost effective because it limits the number of selective neck dissections. Kosuda et al,11 basing their study on the Japanese National Insurance Reimbursement System, estimated that it yielded cost savings of $1,200 US dollars per patient. Lymphoscintigraphic SN detection may have a role in the management of squamous cell carcinoma of the head and neck. Prospective, randomized clinical trials

Table 2. RESULTS OF STUDIES USING THE SENTINEL NODE TECHNIQUE

Study

No. Patients/or Necks

Present study (2004) Hyde et al, 20036 Werner et al, 200212 Shoaib et al, 20015 Kosuda et al, 200311 Ross et al, 200213 Barzan et al, 200214 Taylor et al, 200115 Stoeckli et al, 200116 Mozzillo et al, 200117 Fang et al, 200118 Dunne et al, 200119

25/35 19 43 37/40 11 48/57 31 9 19 41 51 38

SN Not Found

SN⫺ND⫺

SN⫹ND⫺

SN⫹ND⫹

SN⫺ND⫹

1 0 0 4

28 15 38 18

1 3 0

5

28

5 0 10 17 4 15

0 0 2 3

5 13 35 35 32

4 6 5 9 6

0 0 0 2 0

1 1 0 1 0 1 1 0 0 0 2 0

Abbreviations: SN, sentinel node; ND, neck dissection, no metastasis; ⫹, metastasis. Werner, partial result as N1 included in study but not included in this table. Payoux et al. Sentinel Node in Squamous Cell Carcinoma. J Oral Maxillofac Surg 2005.

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are necessary before recommending the technique for widespread use.

References 1. Byers RM, Clayman GL, McGill D, et al: Selective neck dissections for squamous carcinoma of the upper aerodigestive tract: Patterns of regional failure. Head Neck 21:499, 1999 2. Ferlito A, Shaha AR, Rinaldo A: The incidence of lymph node micrometastases in patients pathologically staged N0 in cancer of oral cavity and oropharynx. Oral Oncol 38:3, 2002 3. Laverick S, Lowe D, Brown JS, et al: The impact of neck dissection on health-related quality of life. Arch Otolaryngol Head Neck Surg 130:149, 2004 4. Ross GL, Shoaib T, Soutar DS, et al: The First International Conference on Sentinel Node Biopsy in Mucosal Head and Neck Cancer and adoption of a multicenter trial protocol. Ann Surg Oncol 9:406, 2002 5. Shoaib T, Soutar DS, MacDonald DG, et al: The accuracy of head and neck carcinoma sentinel lymph node biopsy in the clinically N0 neck. Cancer 91:2077, 2001 6. Hyde NC, Prvulovich E, Newman L, et al: A new approach to pre-treatment assessment of the N0 neck in oral squamous cell carcinoma: The role of sentinel node biopsy and positron emission tomography. Oral Oncol 39:350, 2003 7. Stoeckli SJ, Pfaltz M, Steinert H, et al: Histopathological features of occult metastasis detected by sentinel lymph node biopsy in oral and oropharyngeal squamous cell carcinoma. Laryngoscope 112:111, 2002 8. Hermanek P, Hutter RV, Sobin LH, et al: International Union Against Cancer. Classification of isolated tumor cells and micrometastasis. Cancer 86:2668, 1999 9. Nieuwenhuis EJ, Colnot DR, Pijpers HJ, et al: Lymphoscintigraphy and ultrasound-guided fine needle aspiration cytology of

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sentinel lymph nodes in head and neck cancer patients. Recent Results Cancer Rey 157:206, 2000 Hoft S, Muhle C, Brenner W, et al: Fine-needle aspiration cytology of the sentinel lymph node in head and neck cancer. J Nucl Med 43:1585, 2002 Kosuda S, Kusano S, Kohno N, et al: Feasibility and costeffectiveness of sentinel lymph node radiolocalization in stage N0 head and neck cancer. Arch Otolaryngol Head Neck Surg 129:1105, 2003 Werner JA, Dunne AA, Ramaswamy A, et al: Number and location of radiolabeled, intraoperatively identified sentinel nodes in 48 head and neck cancer patients with clinically staged N0 and N1 neck. Eur Arch Otorhinolaryngol 259:91, 2002 Ross G, Shoaib T, Soutar DS, et al: The use of sentinel node biopsy to upstage the clinically N0 neck in head and neck cancer. Arch Otolaryngol Head Neck Surg 128:1287, 2002 Barzan L, Sulfaro S, Alberti F, et al: Gamma probe accuracy in detecting the sentinel lymph node in clinically N0 squamous cell carcinoma of the head and neck. Ann Otol Rhinol Laryngol 111:794, 2002 Taylor RJ, Wahl RL, Sharma PK, et al: Sentinel node localization in oral cavity and oropharynx squamous cell cancer. Arch Otolaryngol Head Neck Surg 27:970, 2001 Stoeckli SJ, Steinert H, Pfaltz M, et al: Sentinel lymph node evaluation in squamous cell carcinoma of the head and neck. Otolaryngol Head Neck Surg 125:221, 2001 Mozzillo N, Chiesa F, Botti G, et al: Sentinel node biopsy in head and neck cancer. Ann Surg Oncol 8:103S, 2001 (suppl 9) Fang J, Wei X, Li S: [Sentinel lymph node biopsy in head and neck cancer patients]. Zhonghua Zhong Liu Za Zhi 23:431, 2001 Dunne AA, Jungclas H, Werner JA: Intraoperative sentinel node biopsy in patients with squamous cell carcinomas of the head and neck–Experiences using a well-type NaI detector for gamma ray spectroscopy. Otolaryngol Pol 55:127, 2001